Modulation of the slow/common gating of CLC channels by intracellular cadmium

Yawei Yu, Ming Feng Tsai, Wei Ping Yu, Tsung-Yu Chen

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Members of the CLC family of Cl- channels and transporters are homodimeric integral membrane proteins. Two gating mechanisms control the opening and closing of Cl- channels in this family: fast gating, which regulates opening and closing of the individual pores in each subunit, and slow (or common) gating, which simultaneously controls gating of both subunits. Here, we found that intracellularly applied Cd2+ reduces the current of CLC-0 because of its inhibition on the slow gating. We identified CLC-0 residues C229 and H231, located at the intracellular end of the transmembrane domain near the dimer interface, as the Cd2+-coordinating residues. The inhibition of the current of CLC-0 by Cd2+ was greatly enhanced by mutation of I225W and V490W at the dimer interface. Biochemical experiments revealed that formation of a disulfide bond within this Cd2+-binding site is also affected by mutation of I225W and V490W, indicating that these two mutations alter the structure of the Cd2+-binding site. Kinetic studies showed that Cd2+ inhibition appears to be state dependent, suggesting that structural rearrangements may occur in the CLC dimer interface during Cd2+ modulation. Mutations of I290 and I556 of CLC-1, which correspond to I225 and V490 of CLC-0, respectively, have been shown previously to cause malfunction of CLC-1 Cl-channel by altering the common gating. Our experimental results suggest that mutations of the corresponding residues in CLC-0 change the subunit interaction and alter the slow gating of CLC-0. The effect of these mutations on modulations of slow gating of CLC channels by intracellular Cd2+ likely depends on their alteration of subunit interactions.

Original languageEnglish (US)
Pages (from-to)495-508
Number of pages14
JournalJournal of General Physiology
Issue number6
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Physiology


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